Project Abstract Our skeleton provides us with strength and mobility, and it also serves as a major reservoir of inorganic ions. Abnormalities in accumulation of bone mass or other aspects of development of the skeleton, as well as in the remodeling processes that occur throughout adult life, can lead to severe diseases, including osteoporosis and osteopetrosis. Osteoporosis in particular is one of the most important diseases affecting the elderly in the developed world. It is characterized by low bone mass and reduced mineral content. The major clinical consequence of osteoporosis is bone fragility and an increased susceptibility to fractures, which are associated with enormous costs and substantial morbidity and mortality. Knowledge about the molecular pathways controlling bone development and remodeling is thus of major clinical importance. The development of the skeleton and maintenance of proper bone mass and mineralization is regulated by several families of molecules, which include members of the Fibroblast Growth Factor (FGF), Insulin-like Growth Factor (IGF), and Transforming Growth Factor-Beta/Bone Morphogenetic Protein (TGF-Beta/BMP) signaling pathways. However, the mechanisms by which this control is achieved are incompletely understood, and the studies described in this proposal focus on the role of Sprouty2 (Spry2), a member of the Sprouty gene family, in regulation of bone biology. Sprouty genes encode molecules that antagonize signaling by FGF receptors as well as other receptor-tyrosine kinases (RTKs). The experiments in this R03 application are based on our recent finding that mice in which the Spry2 gene has been inactivated have smaller and undermineralized bones. The goal of this application is to build on the preliminary observations that loss of Spry2 function leads to abnormalities in bone in order to gain mechanistic insights into signaling pathways that regulate bone quality. PUBLIC HEALTH RELEVANCE: Abnormal bone mineralization or bone mineral density can lead to severe diseases such as osteoporosis and osteopetrosis. Knowledge about the molecular pathways controlling bone formation and mineralization is thus of major clinical importance. The experiments in this R03 application will enhance our understanding of these pathways.